Project Summary Dysregulated immune responses to luminal bacteria in the intestine are largely responsible for the chronic nature of inflammatory bowel disease (IBD). Attenuating the inflammatory response via immunomodulators and/or biologics represent the majority of therapeutic strategies to induce remission. However, many patients either do not respond and those that initially do often stop responding. Restoring immune tolerance by increasing regulatory T cell (Treg) numbers or improving Treg function may be a viable strategy to achieve long-term remission. The PI?s K01 award has focused on strategies to expand Tregs in vivo to prevent experimental colitis in humanized mice. In the course of these studies, the cytokine interleukin-23 (IL-23) was upregulated in murine and human antigen presenting cells. Consistent with a role for IL-23 in IBD, variants in IL23R have been linked to IBD susceptibility. Furthermore, a recent phase 3 clinical trial in patients with Crohn?s disease targeted the p40 subunit of IL-23 (also shared with IL-12) and reported significant improvement in both induction and maintenance of clinical response and remission over placebo. Although macrophage and dendritic cells in the intestine are the source of IL-23, expression of IL-23R is generally restricted to lymphocytes and type 3 innate lymphoid cells (ILC3s). In this proposal, we will determine the role of IL-23R in Tregs in intestinal immune homeostasis and during inflammation using mice harboring floxed Il23r alleles combined with a Cre recombinase driven by the endogenous Foxp3 promotor. In Aim 1, we will determine the role of IL-23R in FOXP3+ Tregs during inflammation and inflammation-associated carcinogenesis. In Aim 2, we will define the transcriptional, metabolic, and signaling networks/pathways modulated by IL-23R signaling in intestinal FOXP3+ cells. Overall, these studies explore in detail how IL-23R differentially impacts mucosal immunity and it?s role during inflammation that will inform future therapeutic strategies for IBD and colon cancer. This proposal will further advance the independent studies of the PI and facilitate his transition as a successful investigator and leader in the field of mucosal immunology and will provide sufficient published and preliminary data to facilitate a highly competitive application for a R01 grant application as an early-stage investigator.